Azmacort

CLINICAL PHARMACOLOGY

Triamcinolone acetonide is a more potent derivative of triamcinolone. Although triamcinolone itself is approximately one to two times as potent as prednisone in animal models of inflammation, triamcinolone acetonide is approximately 8 times more potent than prednisone.

The precise mechanism of the action of glucocorticoids in asthma is unknown.
However, the inhaled route makes it possible to provide effective local anti-inflammatory
activity with reduced systemic corticosteroid effects. Though highly effective
for asthma, glucocorticoids do not affect asthma symptoms immediately. While
improvement in asthma may occur as soon as one week after initiation of Azmacort (triamcinolone acetonide (inhalation aerosol))
Inhalation Aerosol therapy, maximum improvement may not be achieved for 2 weeks
or longer.

Based upon intravenous dosing of triamcinolone acetonide phosphate ester, the half-life of triamcinolone acetonide was reported to be 88 minutes. The volume of distribution (Vd) reported was 99.5 L (SD ± 27.5) and clearance was 45.2 L/hour (SD ± 9.1) for triamcinolone acetonide. The plasma half-life of glucocorticoids does not correlate well with the biologic half-life.

The pharmacokinetics of radiolabeled triamcinolone acetonide [14C]
were evaluated following a single oral dose of 800 mcg to healthy male volunteers.
Radiolabeled triamcinolone acetonide was found to undergo relatively rapid absorption
following oral administration with maximum plasma triamcinolone acetonide and
[14C]-derived radioactivity occurring between 1.5 and 2 hours. Plasma
protein binding of triamcinolone acetonide appears to be relatively low and
consistent over a wide plasma triamcinolone acetonide concentration range as
a function of time. The overall mean percent fraction bound was approximately
68%.

The metabolism and excretion of triamcinolone acetonide were both rapid and
extensive with no parent compound being detected in the plasma after 24 hours
post-dose and a low ratio (10.6%) of parent compound AUC0-∞
to total [14C] radioactivity AUC0-∞. Greater than
90% of the oral [14C]-radioactive dose was recovered within 5 days
after administration in 5 out of the 6 subjects in the study. Of the recovered
[14C]-radioactivity, approximately 40% and 60% were found in the
urine and feces, respectively.

Three metabolites of triamcinolone acetonide have been identified. They are 6β- hydroxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β- hydroxytriamcinolone acetonide. All three metabolites are expected to be substantially less active than the parent compound due to (a) the dependence of anti-inflammatory activity on the presence of a 21-hydroxyl group, (b) the decreased activity observed upon 6-hydroxylation, and (c) the markedly increased water solubility favoring rapid elimination. There appeared to be some quantitative differences in the metabolites among species. No differences were detected in metabolic pattern as a function of route of administration.

Clinical Trials

Double-blind, placebo-controlled efficacy and safety studies have been conducted in asthma patients with a range of asthma severities, from those patients with mild disease to those with severe disease requiring oral steroid therapy.

The efficacy and safety of Azmacort (triamcinolone acetonide (inhalation aerosol)) Inhalation Aerosol given twice daily
was demonstrated in two placebo-controlled clinical trials. In two separate
studies, 222 asthmatic patients were randomized to receive either Azmacort (triamcinolone acetonide (inhalation aerosol))
Inhalation Aerosol 300 mcg twice daily or matching placebo for a treatment period
of 6 weeks. Patients were adult asthmatics who were using inhaled beta2-agonists
on more than an occasional basis (at least three times weekly), either without
or with inhaled corticosteroids, for control of their asthma symptoms. For the
combined studies, 48% (52/109) patients randomized to placebo and 41% (46/113)
patients randomized to Azmacort (triamcinolone acetonide (inhalation aerosol)) Inhalation Aerosol treatment were previously
treated with inhaled corticosteroids.

Results of weekly lung function tests (FEV1) from one of these trials
is presented graphically below. Results of the second study are presented in
tabular form as the changes in asthma measures from baseline to the end of the
treatment period.